The Urgent Need for Optimal Monitoring of Metabolic Adverse Effects in Children and Youngsters Who Take On-label or Off-label Antipsychotic Medication

Abstract

Over the last 2 decades, there has been increasing widespread use of second-generation antipsychotic (SGA) medications in nonpsychotic pediatric populations in the United States and Europe. 1-3 As the ubiquity of SGA drugs in treatment plans for these children and adolescents grows, so does the controversy surrounding them. Antipsychotic medications can induce cardiometabolic abnormalities (such as obesity, hyperglycemia, and dyslipidemia) that are associated with an increased risk of cardiovascular disease and type 2 diabetes mellitus (DM). 3-5 These adverse effects tend to appear faster and to a greater extent in children and adolescents than in adults. 4 In this vulnerable population, roughly the same hierarchy for risk of weight gain with these agents has been identified (with olanzapine having the highest risk, risperidone showing an intermediate risk, and aripiprazole having less effect on body weight) but at a higher rate. 4,5 Generally, this weight gain is rapid during the first few weeks or months of medication use, slows gradually thereafter, and often reaches a plateau within 1 year. 5 Although the occurrence of new cases of DM in antipsychotic-exposed youths remains small, SGA-treated children nevertheless have a 2-fold to 3-fold increased risk of developing type 2 DM compared with SGAnaive children. This risk increases with higher cumulative doses (particularly with olanzapine), longer treatment duration, and adjunctive antidepressant use, and it seems to remain high for a certain period of time after discontinuation. 3,6 High interindividual variability of these adverse effects among patients treated with a given agent suggests that underlying biological or genetic factors predispose children to metabolic adverse effects during SGA treatment. 5 This explains why not all children and adolescents show these adverse effects. Although these adverse effects have been known for a while, no prospective randomized clinical trial has focused on adverse antipsychotic effects on direct measures of both adiposity and insulin sensitivity in antipsychotic-naive children until recently. In this issue of JAMA Psychiatry, Nicol et al 7 used gold-standard measures of adiposity (dual-energy x-ray absorptiometry and magnetic resonance imaging) and insulin sensitivity (a hyperinsulinemic-euglycemic clamp) and found that 12 weeks of treatment with low-dose olanzapine, risperidone, or aripiprazole in children with disruptive behavioral disorders who were antipsychotic-naive produced rapid-onset adverse changes in adiposity and insulin, with larger increases

Association of Antipsychotic Treatment With Risk of Unexpected Death Among Children and Youths

“…The study findings seem to reinforce existing guidelines for improving the outcomes of antipsychotic therapy in children and youths. 5,65 These guidelines include restriction to indications for which there is good evidence of efficacy, adequate trial of alternatives including psychosocial interventions when possible, cardiometabolic assessment before treatment and monitoring after treatment, and limiting therapy to the lowest dose and shortest duration possible.…”

Lurasidone compared to other atypical antipsychotic monotherapies for adolescent schizophrenia: a systematic literature review and network meta-analysis

“…As adolescents are particularly susceptible to atypical antipsychotic-induced weight gain, increased metabolic monitoring is urgently recommended for improving treatment outcomes [38][39][40]. Weight gain may decrease medication adherence [41,42].…”

Impact of Psychotropic Medication Effects on Obesity and the Metabolic Syndrome in People With Serious Mental Illness

“…Screening, assessment, and management of metabolic aspects in patients with SMI remain poor, even in developed countries ( 4 , 11 , 126 ). It is therefore imperative that psychiatrists, physical health specialists and general practitioners are aware of the interaction between SMI, psychotropics and metabolic abnormalities and collaborate in the integrated care for these patients so that they can receive optimal treatment.…”

“…As antipsychotic-associated DM is clearly a major issue in adults, it emphasizes the need for an even more judicious use of this class of medications in children and adolescents ( 4 , 10 , 114 ). Children who are prescribed a SGA have a 2–3 times higher risk of developing type 2 DM, compared with SGA-naive children.…”

“…Higher cumulative doses (particularly with olanzapine), longer treatment duration, and adjunctive antidepressant use may increase this risk even further, which seems to remain high for a certain period of time after discontinuation ( 114 – 116 ). The metabolic adverse effects during SGA treatment more than likely are mediated by biological or genetic factors, explaining why some children and adolescents are more susceptible to these adverse effects than others ( 1 , 4 ).…”